This is an R21 application for a pilot study of the prodromal (i.e., pre-manic) phase of adult onset bipolar disorder. Pilot work is considered essential for demonstrating the viability of the prodromal concept in bipolar disorder, which remains controversial and little studied. Subjects identified as prodromal constitute a new risk population for bipolar disorder, one that is based on the presence of early subthreshold clinical signs and symptoms in contrast with the more traditional genetic high risk approach which selects subjects according to family history of illness. Our research group was among the first to apply a clinical high risk (CHR) approach to intervention in schizophrenia, now widely adopted throughout the field. Like schizophrenia, bipolar disorder is a chronic, highly debilitating illness with a presumed developmental course. It is thus proposed that a CHR strategy tailored specifically for the pre-mania prodrome might be effective in altering the course of illness. At the same time, however, it is clear that bipolar disorder presents unique challenges in the identification of a prodromal phase. It is therefore essential to do extensive pilot research to adapt the CHR strategy to the specific nature of the bipolar illness. The proposed two year pilot study will include four groups of 40 adolescents each, ranging in age from 13-18. These groups include: 1) CHR for Mania (CHR-M), the at-risk group of primary interest, characterized by two or more manic symptoms at subthreshold intensity, 2) a patient comparison group, matched for age, gender and SES, consisting of adolescents diagnosed with bipolar I within the previous two years, 3) adolescents at clinical high risk for schizophrenia (CHR-SZ), and 4) matched healthy controls. Groups 3 and 4 will be available, at no cost to the proposed application, through the independently funded RAP parent program, an ongoing study of adolescents at risk for schizophrenia. The goals of this pilot study are to: 1) establish feasibility in recruiting a sample of CHR-M adolescents; 2) provide preliminary cross-sectional validation of the developmental prodromal construct; 3) conduct short-term six-month follow-ups to establish the stability of selected endophenotypes and risk factors; 4) assess specificity to bipolar disorder by comparing CHR-M and CHR-SZ subjects and 5) preliminarily determine short term (6 month) clinical outcome. The data collected is the essential first step for launching a larger, prospective study of the bipolar prodrome and, in the long term, for initiating effective early intervention. PUBLIC HEALTH RELEVANCE: Prevention of bipolar disorder will relieve personal and family hardship and economic loss to society. This naturalistic pilot study represents a critical first step towards prevention by providing evidence that clinical and endophenotypic risk factors can be identified prior to the onset of full bipolar disorder. Early identification and study of individuals at high-risk for bipolar disorder will help elucidate the neurodevelopmental underpinnings of the disorder and lead to targeted preventative interventions. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]